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The transcription factors TFE3 and TFEB amplify p53 dependent transcriptional programs in response to DNA damage

  1. Eutteum Jeong
  2. Owen A Brady
  3. Jose A Martina
  4. Mehdi Pirooznia
  5. Iker Tunc
  6. Rosa Puertollano  Is a corresponding author
  1. National Heart, Lung, and Blood Institute, National Institutes of Health, United States
Research Article
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Cite this article as: eLife 2018;7:e40856 doi: 10.7554/eLife.40856

Abstract

The transcription factors TFE3 and TFEB cooperate to regulate autophagy induction and lysosome biogenesis in response to starvation. Here we demonstrate that DNA damage activates TFE3 and TFEB in a p53 and mTORC1 dependent manner. RNA-Seq analysis of TFEB/TFE3 double-knockout cells exposed to etoposide reveals a profound dysregulation of the DNA damage response, including upstream regulators and downstream p53 targets. TFE3 and TFEB contribute to sustain p53-dependent response by stabilizing p53 protein levels. In TFEB/TFE3 DKOs, p53 half-life is significantly decreased due to elevated Mdm2 levels. Transcriptional profiles of genes involved in lysosome membrane permeabilization and cell death pathways are dysregulated in TFEB/TFE3-depleted cells. Consequently, prolonged DNA damage results in impaired LMP and apoptosis induction. Finally, expression of multiple genes implicated in cell cycle control is altered in TFEB/TFE3 DKOs, revealing a previously unrecognized role of TFEB and TFE3 in the regulation of cell cycle checkpoints in response to stress.

Article and author information

Author details

  1. Eutteum Jeong

    Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Owen A Brady

    Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jose A Martina

    Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Mehdi Pirooznia

    Bioinformatics and Computational Biology Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Iker Tunc

    Bioinformatics and Computational Biology Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Rosa Puertollano

    Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, United States
    For correspondence
    puertolr@mail.nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1106-5489

Funding

National Institutes of Health

  • Eutteum Jeong
  • Owen A Brady
  • Jose A Martina
  • Mehdi Pirooznia
  • Iker Tunc
  • Rosa Puertollano

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Hong Zhang, Institute of Biophysics, Chinese Academy of Sciences, China

Publication history

  1. Received: August 6, 2018
  2. Accepted: December 3, 2018
  3. Accepted Manuscript published: December 6, 2018 (version 1)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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